Leukotriene D4 activates mitogen-activated protein kinase through a protein kinase Calpha-Raf-1-dependent pathway in human monocytic leukemia THP-1 cells.
Leukotriene D4 (LTD4) is a major lipid mediator involved in inflammatory and allergic disorders including bronchial asthma. Despite its potent biological activity, little is known about the receptor and intracellular signaling pathways. Here we analyzed the signal transduction mechanisms through LTD4 receptors using human monocytic leukemia THP-1 cells. When these cells were stimulated with LTD4, intracellular calcium concentration was increased and mitogen-activated protein kinase (MAP kinase) was activated severalfold. This activation was inhibited by staurosporine or GF109203X treatment or abolished by protein kinase C depletion. Cytosolic protein kinase Calpha was translocated to the membrane, and Raf-1 was activated by LTD4 treatment in a similar time course. LTD4-induced Raf-1 activation was diminished by protein kinase C depletion in the cells. A chemotactic response of THP-1 cells toward LTD4 was observed which was inhibited by pertussis toxin (PTX) pretreatment. Thus, LTD4 has at least two distinct signaling pathways in THP-1 cells, a PTX-insensitive mitogen-activated protein kinase activation through protein kinase Calpha and Raf-1 and a PTX-sensitive chemotactic response. This cellular signaling can explain in part the versatile activities of LTD4 in macrophages under inflammatory and allergic conditions.
Hoshino
M
M
Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113, Japan.
Izumi
T
T
Shimizu
T
T
D001692:Biological Transport; D002118:Calcium / Q000032:analysis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002451:Cell Compartmentation; D002634:Chemotaxis, Leukocyte; D000242:Cyclic AMP / Q000032:analysis; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007951:Leukemia, Myeloid; D017998:Leukotriene D4 / Q000494:pharmacology*; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D018077:Receptors, Leukotriene / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; D000242:Cyclic AMP; D019908:Proto-Oncogene Proteins c-raf; C496628:PRKCA protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C083169:leukotriene D4 receptor; D002118:Calcium